Effects of prior oral contraceptive use and soy isoflavonoids on estrogen-metabolizing cytochrome P450 enzymes.
Estrogen exposure and metabolism may play an important role in the development of estrogen-sensitive cancers in postmenopausal women. In this study we investigated whether past oral contraceptive (OC) administration or current dietary isoflavonoids (IF) affected expression and/or activity of steroid hormone-metabolizing cytochrome P450 (CYP) enzymes using complementary primate and cell culture models. One-hundred-eighty-one female cynomolgus macaques were randomized to receive OC or nothing for 26 months premenopausally, then ovariectomized and randomized to one of three diets for 36 months: an IF-depleted soy protein isolate (Soy-) diet, a Soy diet with IF (Soy+), or a Soy- diet supplemented with conjugated equine estrogens (CEE). Prior OC-treatment significantly reduced CYP gene expression in the mammary gland (< or =60% of OC-). Dietary IFs had no effect on CYP expression, while CEE-treatment decreased CYP1A1 and increased CYP3A4 mRNA in a tissue-specific manner. For in vitro studies, we measured effects of the isoflavonoids genistein, daidzein and equol on CYP activity using intact V79 cells stably transfected to express CYP1A1, CYP1B1, or CYP3A4. All three IFs significantly altered CYP activity in a dose-dependent and isoform-specific manner (20-95% inhibition versus controls). These results suggest potential mechanisms for prior OC and dietary IF effects on cancer risk in estrogen-responsive tissues.
Scott
L M
LM
Department of Pathology, Section on Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Durant
P
P
Leone-Kabler
S
S
Wood
C E
CE
Register
T C
TC
Townsend
A
A
Cline
J M
JM
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D002460:Cell Line; D003276:Contraceptives, Oral / Q000494:pharmacology*; D018899:CpG Islands / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D065633:Cytochrome P-450 CYP1B1; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004032:Diet; D060754:Equol; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology; D007529:Isoflavones / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D008252:Macaca fascicularis; D008321:Mammary Glands, Animal / Q000201:enzymology; D012333:RNA, Messenger / Q000378:metabolism
C007610:4',7-dihydroxy-3,4-dihydroisoflavone; D003276:Contraceptives, Oral; D007529:Isoflavones; D012333:RNA, Messenger; D060754:Equol; C004742:daidzein; D019833:Genistein; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D051544:Cytochrome P-450 CYP3A